Structure-Based Drug Design of Novel Triaminotriazine Derivatives as Orally Bioavailable IDH2 R140Q Inhibitors with High Selectivity and Reduced hERG Inhibitory Activity for the Treatment of Acute Myeloid Leukemia.

Neomorphic IDH2 R140Q mutation is commonly found in acute myeloid leukemia (AML), and inhibiting its activity has been validated as an effective treatment for AML. Herein, we report a series of highly potent and selective IDH2 R140Q inhibitors. Among them, compound 36 was identified as the most promising inhibitor, with an IC 50 value of 29 nM and more than 490-fold selectivity over wild-type IDH2. The compound significantly suppressed D2HG production (IC 50 = 10 nM) and induced differentiation in TF-1/IDH2 R140Q cells. Furthermore, it showed reasonable pharmacokinetic properties with high bioavailability ( F = 90.3%) and an appropriate half-life ( T 1/2 = 6.4 h). In vivo , oral administration of compound 36 at a dose of 25 mg/kg effectively reduced D2HG levels in the tumor of TF-1/IDH2 R140Q xenograft mouse model. Besides, compound 36 displayed little effect on the hERG current. These results suggest that compound 36 has the potential to be an efficacious treatment for AML.